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Toxicological information

Carcinogenicity

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Description of key information

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Toxicological relevance of the counterion “sulfate”

The registrant is of the opinion that the toxicity of strontium sulfate is driven by the strontium moiety and that the sulfate anion does not contribute to the overall toxicity of the substance strontium sulfate to any relevant extent, for the following reasons:

Sulfate anions are abundantly present in the human body in which they play an important role for the ionic balance in body fluids. Sulfate is required for the biosynthesis of 3′-phosphoadenosine-5′-phosphosulfate (PAPS) which in turn is needed for the biosynthesis of many important sulfur-containing compounds, such as chondroitin sulfate and cerebroside sulfate. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) concludes that the few available studies in experimental animals do not raise any concern about the toxicity of the sulphate ion in sodium sulphate. Sodium sulphate is also used clinically as a laxative. In clinical trials in humans using 2-4 single oral doses of up to 4500 mg sodium sulphate decahydrate per person (9000 – 18000 mg per person), only occasional loose stools were reported. These doses correspond to 2700 - 5400 mg sulphate ion per person. High bolus dose intake of sulphate ion may lead to gastrointestinal discomfort in some individuals. No further adverse effects were reported (JECFA 2000, 2002). This position was adopted by the European Food Safety Authority (EFSA 2004) without alteration.

Based on the above information, one can therefore safely assume that the sulfate anion in strontium sulfate does not contribute to the overall toxicity of strontium, sulfate. It is concluded that only the effect of “strontium” is further considered in the human health hazard assessment of strontium sulfate.

Read across concept:

(i) from SrRanelate to SrSO4:

The toxicity of strontium substances such as strontium sulfate can reasonably assumed to be determined by the availability of strontium ions in solution. Both substances (strontium ranelate and strontium sulfate) are “ moderately soluble” to "very soluble" (170 mg SrSO4/L at 37°C/ pH 1.5and 6.74 g SrRenelate/L at 37°C/ pH 3.8) at low pH (pH in the gastrointestinal tract is ~1.5). Hence, it can be concluded that possible adverse effects observed with SrRanelate are certainly representative of possible similar effects to be expected in SrSO4 exposure.

(ii) from SrCl2to SrSO4:

The toxicity of strontium substances such as strontium sulfate can reasonably assumed to be determined by the availability of strontium ions in solution. As a first surrogate for bioavailability, the water solubility of a test substance may be used. Strontium chloride is highly water soluble with ~538 g/L at pH ~7, whereas strontium sulfate is moderately soluble (~125 mg/L at pH ~ 6.5). Hence, any read across from strontium chloride to strontium sulfate is inherently very conservative.

 

(iii) from Sr(NO3)2to SrSO4:

The toxicity of strontium substances such as strontium sulfate can reasonably assumed to be determined by the availability of strontium ions in solution. As a first surrogate for bioavailability, the water solubility of a test substance may be used. Strontium nitrate is highly water soluble with ≤ 802 g/L at pH ~ 7, whereas strontium sulfate is moderately soluble (~125 mg/L at pH ~ 6.5). Hence, any read across from strontium nitrate to strontium sulfate is inherently very conservative.

According to the EMEA report 2005 (see study summary "s_EMEA_2005 -rat" and "s_EMEA_2005 -mice") the results of a 105 weeks carcinogenicity in male and female rats, indicate some increased incidences of C-cell carcinoma in thyroids of male rats in the low (LD) and high dose (HD) groups. It is stated that it cannot completely be excluded that a subtle increase in plasma cation levels may have, in some individual rats, affected the progression of thyroid C-cell hyperplasia/adenoma to carcinoma. However, taking the totality of the data into account, there is no clear evidence that the finding of increased incidences of C-cell carcinoma in LD and HD males in the main carcinogenicity study in the rat are related to strontium ranelate treatment. Moreover, there are some differences between human and rat with respect to calcitonin regulation, such as the age-related increased increase in calcitonin in rats, whereas the opposite occurs with increasing age in humans, which indicate that the tumour findings are of minor clinical relevance. In addition, the incidence of C-cell tumours was not increased in female rats and in male and female mice, and male F344 rats treated over 52 weeks with doses as in the carcinogenicity studies had no increase in thyroid C-cell proliferative lesions. In conclusion and in accordance with theregulation (EC) 1907/2006 Annex X column 2 a carcinogenicity study is not proposed since there is no evidence that the substance has mutagenetic or carcinogenetic effects. The data provided in this section are sufficient for the evaluation and classification / non classification of the substance.

Furthermore, there is an absence of any published evidence on the formation of tumours in humans after exposure to stable strontium compounds(i.e., strontium nitrate and strontium chloride). Information is available on the action of strontium in in-vivo and in-vitro screening systems for the prediction of mutagenicity or carcinogenicity of metal salts. The DNA synthesis in nuclear epithelia of kidney and liver was not inhibited by intra-peritoneal injection of strontium nitrate to mice (s_Amlacher_1983). Investigations in a in-vitro screening system showed that strontium chloride did not affect the accuracy of the DNA synthesis (s_Sirover, 1976).


Justification for selection of carcinogenicity via oral route endpoint:
see "discussion" below

Justification for classification or non-classification

Taken together, the results discussed in the above area it can be concluded that strontium is not identified as potential mutagen or carcinogen. Hence, no classification and labelling of strontium sulfate as carcinogenetic substance is necessary.